包载纳米氧化铈促进脐带MSCs胞外囊泡修复梗死心肌的机制研究

如何有效地修复梗死心肌是心血管领域的“圣杯”，间充质干细胞(MSCs)胞外囊泡（EV）极具潜力。团队前期发现心梗诱发的氧化应激可能损伤EV脂膜结构，减少功能内容物含量，提示抗氧化保护可能是优化EV治疗心梗的关键。氧化铈是新型抗氧化纳米酶，我们新近原创MSCs-EV包载纳米氧化铈体系，发现在双氧水诱导的氧化应激损伤中，包载氧化铈可以显著保护MSCs-EV膜结构，上调miR-126/音猬因子，提升对内皮细胞功能的保护。故推测：包载氧化铈可能通过抗氧化保护EV脂膜与选择性装载miR-126/音猬因子的机制增强MSCs-EV的心梗治疗能力。本项目拟结合生物学、医学与工程学技术，旨在：1）建立MSCs-EV包载纳米氧化铈的技术方法；2）明确包载氧化铈是否提升MSCs-EV的心梗治疗作用;3）阐明包载氧化铈调控MSCs-EV心梗治疗作用的机制。本项目将为MSCs-EV治疗心梗提供新依据、新策略。

Repairing the infarcted heart is the Holy Grail in cardiovascular research. Extracellular vesicles derived from mesenchymal stem cell (MSCs-EV) is promising for cardiac repair post myocardial infarction (MI). It’s well known that the harmful oxidative stress was induced after MI. Previously, we found oxidative stress damage the membrane structure and inner content of EV, suggesting the key role of antioxidant protection in treating ischemic injury using EV. Thus, in this project we suggest a band new strategy of EV optimization: the nanoceria loading. The cerium oxide nanoparticles (CONPs) is novel antioxidant nanozyme. Loading CONPs protected the membrane structure and increased the level of miR-126 and Sonic hedgehog (SHH) in MSCs-EV, MSCs-EV-loaded CONPs showed better protection on endothelial cell function under oxidative stress. We then hypothesize that loading CONPs improve MSCs-EV therapy on MI through the antioxidant protection of EV membrane and the selective loading of miR-126/SHH into EV. This project combined biological, medical and engineering technologies to study the following scientific questions: 1) building MSCs-EV-loaded CONPs system; 2) if loading CONPs improve the therapy of MSCs-EV on MI; 3) elucidating the potential mechanism of CONPs regulating MSCs-EV’s therapeutic efficacy on infarcted myocardium. Our study may provide new evidence and optimization method for the translational application of MSCs-EV in clinic.